The Pharma Innovation Journal 2015; 4(5): 14-20
ISSN: 2277- 7695
TPI 2015; 4(5): 14-20
© 2015 TPI
www.thepharmajournal.com
Received: 20-05-2015
Accepted: 22-06-2015
Priyanka Patel
Department of Pharmaceutics,
SSR College of Pharmacy, Sayli
road, Silvassa, UT of Dadra &
Nagar Haveli. 396230. India.
Kajal Ahir
Department of Pharmaceutics,
SSR College of Pharmacy, Sayli
road, Silvassa, UT of Dadra &
Nagar Haveli. 396230. India.
Vandana Patel
Department of Pharmacognosy,
SSR College of Pharmacy, Sayli
road, Silvassa, UT of Dadra &
Nagar Haveli. 396230. India.
Lata Manani
Department of Pharmacognosy,
SSR College of Pharmacy, Sayli
road, Silvassa, UT of Dadra &
Nagar Haveli. 396230. India.
Chirag Patel
Department of Pharmacology,
SSR College of Pharmacy, Sayli
road, Silvassa, UT of Dadra &
Nagar Haveli. 396230. India.
Correspondence:
Priyanka Patel
Department of Pharmaceutics,
SSR College of Pharmacy, Sayli
road, Silvassa, UT of Dadra &
Nagar Haveli. 396230. India.
 
Drug-Excipient compatibility studies: First step for
dosage form development
Priyanka Patel, Kajal Ahir, Vandana Patel, Lata Manani, Chirag Patel
Abstract
Studies of drug-excipient compatibility represent an important phase in the preformulation stage of the
development of all dosage forms. The potential physical and chemical interactions between drugs and
excipients can affect the chemical, physical, therapeutical properties and stability of the dosage form. The
present review contains a basic mode of drug degradation, mechanism of drug- excipient interaction like
physical, chemical and biopharmaceutical. Different Thermal and Non-thermal method of analysis, Tools
and software for incompatibility is also discussed. Once the type of interaction is determined we can take
further steps to improve the stability of drug and dosage form. From review, we conclude that consequent
use of thermal and non-thermal method provide data for drug- excipient interaction which can further
help in selection of excipient for the development of stable dosage form.
Keywords: Drug-excipient compatibility, thermal method, non-thermal method, interaction,
incompatibility
1. Introduction
A complete characterization and understanding of physicochemical interactions of an active
pharmaceutical ingredient (API) in the dosage forms is an integral part of preformulation stage
of new dosage form development as it is most desirable for consistent efficacy, safety and
stability of a drug product. In a dosage form, an API comes in direct contact with other
components (excipients) of the formulation that facilitate the administration and release of an
active component as well as protect it from the environment. Although excipients are
pharmacologically inert, they can interact with drugs in the dosage form to affect drug product
stability in physical aspects such as organoleptic properties, dissolution slow down or
chemically by causing drug degradation. Careful selection of the excipients are required for a
robust and effective formulation of dosage forms that make administration easier, improve
patient compliance, promote release and bioavailability of the drug and increase its shelf life.
Thus, compatibility screening of an API with excipients or other active ingredients is
recognized as one of the mandatory factors and is at the fore front of drug product science and
technology research [1, 2].
A complete understanding of the physicochemical interactions in dosage forms is expected
under quality by design prototype of drug development. The analytical methods into the initial
steps of preformulation studies have contributed significantly to early prediction, monitoring
and characterization of the API incompatibility to avoid costly material wastage and
considerably reduce the time required to arrive at an appropriate product formulation.
1.1 Incompatibility [3]
 “Inactivation of drug through either decomposition or loss of drug by its conversion to a
less favourable physical or chemical form.” When we mix two or more API and / or
excipient with each other and if they are antagonistic and affect adversely the safety,
therapeutic efficacy, appearance or elegance then they are said to be incompatible.
1.2 Importance of drug excipient compatibility [5, 6]
 Stability of the dosage form can be maximized. Any physical or chemical interaction
between drug and excipient can affect bioavailability and stability of drug.
 It helps to avoid the surprise problems. By performing drug excipient compatibility
studies (DECS) we can know the possible reaction before formulating final dosage form.
 DECS data is essential for IND (investigational new drug) submission. Now, USFDA has
made it compulsory to submit DECS data for any new coming formulation before its
approval.
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 Determine a list of excipient that can be used in final
dosage form.
 To reduce associated side effect of drug due to DECS in
dosage form.
 To overcome problems associated with incorporation of
multiple excipients.
1.3 Excipients [7, 8]
“Pharmaceutical excipients are substance other than
pharmacologically active drug or prodrug in finished dosage
form as to impart specific qualities to them.”
Role of excipient
 Protect, support or enhance stability of the Formulation.
 Bulk up the formulation in case of potent drug for
assisting in formulation of an accurate dosage form.
 Improve patient acceptance.
 Help improve bioavailability of active drug.
 Enhance overall safety and effectiveness of the
formulation during its storage and use.
2. Mode of drug decomposition [9, 10, 11]
Medicinal agents invariably have structural features that
interact with receptors or facilitate metabolic handling. These
predictably confer some degree of liability, making them
vulnerable to degradation (and interaction with other
materials). They are hydrolysis/dehydration,
isomerisation/epimerization decarboxylation, rearrangement
and some kinds of polymerization reactions can be generalized
into a condition that has been called “thermolytic”. These
reactions are generally sensitive to temperature and can be
accelerated by elevating the temperature under various
conditions in the solid state (low and high humidity).
Hydrolytic reactions, can be accelerated both by exposure to
elevated temperature as and by exposure to different pH values
in a broad pH range. Oxidative degradation of pharmaceuticals
is generally the result of autoxidation. It is driven by the
formation of radicals (via initiators such as transition metals,
low levels of peroxides, or molecular oxygen). Photolytic
reactions are initiated by the absorption of photons from
exposure to various sources of light.
2.1. Common modes of degradation are described below-
2.1.1 Hydrolysis-Drugs with functional groups such as esters,
amides, lactones may be susceptible to hydrolytic degradation.
It is probably the most commonly encountered mode of drug
degradation because of the occurrence of such groups in
Table 1: Modes of degradation of medicinal agents
Hydrolysis Oxidation Isomerization
Methyldopa Calcitonin Tetracycline
Procaine Ascorbic acid Vitamin A
Penicillins isoprenaline Adrenaline
3. Mechanism of drug excipient interaction
Exact mechanism of drug excipients interaction is not clear.
However, there are several well documented mechanisms in
the literature. Drug excipients interaction occurs more
frequently than excipient-excipient interaction. Drug-
excipients interaction can either be beneficial or detrimental,
which can be simply classified as-
1. Physical interactions
2. Chemical interactions
~ 15 ~
medicinal agents and ubiquitous nature of water. Water can
also act as a vehicle for interactions or facilitates microbial
growth.
2.1.2. Oxidation
Oxidative degradation is second only to hydrolysis as a mode
of decomposition. In contrast to hydrolysis, oxidative
mechanisms are complex, involving removal of an
electropositive atom, radical or electron or, conversely,
addition of an electronegative moiety. Oxidation reactions can
be catalyzed by oxygen, heavy metal ions and light, leading to
free radical formation. Free radicals react with oxygen to form
peroxy radicals which in turn react with oxidizable compound
to generate additional free radicals to fuel further reactions.
Aldehydes, alcohols, phenols, alkaloids and unsaturated fats
and oils are all susceptible to oxidation.
2.1.3. Isomerization
Isomerization involves conversion of a chemical into its
optical or geometric isomer. Isomers may have different
pharmacological or toxicological properties. For example, the
activity of levo (L) form of adrenaline is 15-20 times greater
than for the dextro (D) form.
2.1.4. Photolysis
Reactions such as oxidation-reduction, ring alteration and
polymerization can be catalyzed or accelerated by exposure to
sunlight or artificial light. Energy absorption is greater at
lower wavelengths and, as many as drugs absorb UV light;
degradation by low wavelength radiation is common.
Exposure to light almost invariably leads to discoloration even
when chemical transformation is modest or even undetectable.
2.1.5. Polymerization
Intermolecular reactions can lead to dimeric and higher
molecular weight species. Concentrated solutions of
ampicillin, an aminopenicillin, progressively form dimer,
trimer and ultimately polymeric degradation products.
Table 1 lists examples of medicinal agents susceptible to such
modes of degradation. Degradation may reflect vulnerability to
environmental stresses such as heat, humidity, light or drug–
drug interactions. Degradation may also be facilitated or
promoted by excipients possessing the requisite functional
groups for interaction, or containing residues that
catalyze/participate in degradation processes. If excipients are
also susceptible to change, this provides additional
possibilities for the generation of species that participate in
break down processes.
Photolysis Polymerization
Riboflavin Ceftazidime
Folic acid Ampicillin
Nifedipine
3. Biopharmaceutical interactions
3.1 Physical interactions: Physical interactions are very
common in dosage form and also difficult to detect. Physical
interactions may or may not involve chemical changes thus
permitting the components in the formulation to retain their
molecular structure. Physical interactions involve change in a
dissolution, solubility, sedimentation rate etc. Physical
interactions can be either beneficial or detrimental to the
product performance which is dependent on its application.
Different physical interactions are as follows:
 
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Table 2: Physical Interaction
Interaction
Complexation:-
Complexing agent binds reversibly with drugs to form
complex. Sometimes insoluble complexes are formed
which lead to slower dissolution and decreased
absorption of drug which is detrimental.
Complexing agents can also be used to increase
bioavailability of poorly water soluble drugs which is
beneficial
Adsorption:-
Adsorption of drug by excipient can lead to reduced
bioavailability as the drug is not available for dissolution.
Adsorption of drug on excipient surface can assist in
increasing surface area of drug available for dissolution
which eventually increases bioavailability.
Solid dispersion:-
This kind of interactions improves the dissolution and
bioavailability of hydrophobic drugs.
Sometimes solid dispersion interactions can result in
slow dissolution of drugs.
Beneficial effect examples Detrimental effect examples
Cyclodextrin is often used to improve Tetracycline formed insoluble
bioavailability of poorly water soluble complex with calcium carbonate
drugs. This increases bioavailability and leading to slower dissolution and
increases rate and extent of drug decreased absorption.
dissolution.
Cetyl Pyridinium chloride cations get
adsorbed on the surface of
Formulation of Indomethacin (NSAID)
magnesium stearate which acts as a
using kaolin as adsorbent increased its
lubricant in tablet containing Cetyl
dissolution rate which leads to increase in
Pyridinium chloride.
bioavailability of drug.
This leads to marked reduction in the
antibacterial activity of the drug.
Improved dissolution rates of drugs like
Solid dispersion product formed due
Piroxicam, Norfloxacin, Nifedipine and
to interaction between Povidone and
Ibuprofen were observed when these drugs
Stearic acid in a capsule showed
were formulated into solid dispersions
slow dissolution of drugs.
using Polyethylene glycol of different
molecular weights.

3.2 Chemical interactions: - Active pharmaceutical
ingredients and excipients react with each other to form
unstable compounds. Several chemical drugs excipient
interactions have been reported in literature which is
mentioned in literature under heading 2. Generally chemical
interactions have a deleterious effect on the formulation hence
such kind of interactions must be usually avoided.
3.3. Biopharmaceutical interactions: These are the
interactions which are observed after administration of the
medication. Interaction of medicine with body fluid influences
the rate of absorption. All excipients interact in physiological
way when they are administered along with active
pharmaceutical ingredients, various examples of
biopharmaceutical interactions are stated as follows:-
3.3.1. Premature breakdown of enteric coat
The enteric coating polymers like cellulose acetate phthalate
and hydroxylpropyl cellulose acetate phthalate, are soluble
more at basic pH, but antacids raise pH of stomach resulting in
breakdown of the enteric coat in stomach and release of active
pharmaceutical ingredient in stomach itself, which results in
degradation of drug in stomach. In case of NSAID’s premature
breakdown of enteric coat may cause side effects like gastric
bleeding.
3.3.2. Interactions due to adjunct therapy
Tetracycline antibiotics form complexes with calcium and
magnesium ions which are quite common excipients in various
formulations which may be administered along with
tetracycline as adjunct therapy the complex so formed is not
absorbed from the G.I.T.
3.3.3. Increase in gastrointestinal motility
Many of the excipients like sorbitol, xylitol, have tendency to
increase the gastrointestinal motility thus reducing the time
available for absorption of drugs like metoprolol.
4. Methods of estimation of drug excipient compatibility [1, 13]
Formulation scientists have explored various thermal and non-
thermal analytical techniques for early prediction of suitable
~ 16 ~
excipients for the dosage forms to minimize or mitigate the
untoward reactions (stability issues) which arise from drug–
excipient incompatibility. Till date no universally accepted
protocol is available for evaluating the compatibility of drug
with other components. However, a flurry of reports have
appeared in the last decade that highlight the use of analytical
tools used in the compatibility screening of APIs in search of
suitable excipients. Frequently used analytical techniques for
prospective compatibility screening studies include thermal
methods such as differential scanning calorimetry, thermo
gravimetric analysis, differential thermal analysis, isothermal
micro calorimetry, hot stage microscopy and other analytical
methods namely powder X-ray diffraction, Fourier transform-
infrared spectroscopy, scanning electron microscopy and high
performance liquid chromatography. Relatively newer
spectroscopic techniques like solid state Nuclear Magnetic
Resonance spectroscopy and near Infrared spectroscopy
having potential applications in the analysis of pharmaceutical
solids, have been extended to study the drug–excipient or drug
moisture interactions that may lead to instability of the active
principles. These techniques vary in their working principles,
mechanical and thermal stress that is applied to the sample,
time of analysis and amount of sample required, sensitivity of
the technique to minute changes, and the necessity of internal
or external standards. Moreover, some of the reported methods
for the assessment of compatibility have poor predictive value
while a few of them possess time consuming exercise in the
pharmaceutical product development. Therefore, combinations
of thermal and non-thermal methods are successful in proper
identification of incompatibility.
Analytical tools for compatibility assessment of APIs
4.1. Thermal methods of analyses
1. Differential scanning calorimetry (DSC)
2. Isothermal microcalorimetry
3. Hot stage microscopy (HSM)
4.2. Spectroscopic techniques
1. Vibrational spectroscopy
2. Powder X-ray diffraction (PXRD).
3. Solid state nuclear magnetic resonance spectroscopy
(ss NMR)
 

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4.3. Microscopic technique
1. Scanning electron microscopy (SEM)
4.4. Chromatographic technique
1. High performance liquid chromatography
4.1 Thermal methods of analyses [2]
Thermal analysis plays a critical role in compatibility
screening studies and has been frequently employed for quick
assessment of physicochemical incompatibility. Conventional
compatibility testing methods require both multiple sample
preparation and long storage times in order to obtain
meaningful results. However, the thermal methods offer
potential advantages over the conventional isothermal stress
testing (IST) techniques. Thermal analysis eliminate the
lengthy storage conditions and method development for all the
active compounds required during IST and allow for a large
number of excipient screening experiments to be performed in
a short duration of time. The results obtained from thermal
techniques are direct indicators of that excipient which are
likely to be compatible, cutting down the conventional
compatibility samples to prepare and thus saving the valuable
time.
4.1.1 Differential scanning calorimetry (DSC) [14, 15]
DSC represents a leading thermal analysis technique that has
been increasingly used for active pharmaceutical ingredient
screening of incompatibilities for over 50 years. In this
technique, the DSC curves of pure components are compared
to the curves obtained from 1:1 physical mixtures. It is
assumed that the thermal properties (melting point, change in
enthalpy, etc.) of blends are the sum of the individual
components if the components are compatible with each other.
An absence, a significant shift in the melting of the
components or appearance of a new exo/endothermic peak
and/or variation in the corresponding enthalpies of reaction in
the physical mixture indicates incompatibility. However, slight
changes in peak shape height and width are expected due to
possible differences in the mixture geometry. DSC stands to
benefit over other conventional techniques in requirement of
short time of analysis and low sample consumption. It also
provides useful indications of the potential problems, so that
an excipient can be rejected at an initial stage of product
development. If the excipient under consideration is
indispensable, the nature of interactions with the active API
can be studied in depth. In spite of all the merits, the
conclusions based on DSC results alone may be misleading
and have to be interpreted carefully.
4.1.2. Isothermal microcalorimetry [16]
Isothermal microcalorimetry has proved to be an invaluable
tool in the realm of solid state pharmaceutics with its
important application in compatibility determination. It works
on the principle that all physical and chemical processes are
accompanied by a heat exchange within their surroundings. It
allows determination of minute amounts of evolved or
absorbed heat and heat flow signals in the range of µW are
easily detectable. Further, micro reaction calorimeter gives
meaningful results without requirement of multiple sample
preparations and long storage times. In a typical compatibility
experiment, a solution, suspension, or solid mixture of API
and excipient is placed in the calorimeter and the thermal
activity (heat flow) at a constant temperature is monitored.
The basic assumption is that the rate of heat production is
proportional to the rate of chemical and/or physical processes
~ 17 ~
taking place in sample. The thermal activity of API and
excipient are measured individually, and then the output of the
blend is compared to the “non-interaction” curve constructed
from the individual components. If an experimentally
significant difference is observed, the excipient is considered
to be potentially incompatible with the API. Because the signal
may be the sum of numerous chemical and physical processes,
one should exercise proper caution before attempting to
correlate the signal with rate of degradation. Instead, the
method should be used as an indicator of potential
incompatibility. Applying these simple testing criteria reduces
the number of samples that must be screened using time
consuming HPLC, X-ray and other methods, thus saving
valuable time and effort during the formulation process.
4.1.3 Hot stage microscopy [17, 18]
Hot stage microscopy (HSM) or thermo microscopy is an
analytical technique which combines the best properties of
thermal analysis and microscopy. Thus, it is a complementary
thermal analysis technique useful for visualizing thermal
events recorded by DSC and TGA as well as a versatile tool
for solid state screening. Although DSC and isothermal
microcalorimetry are considered efficient methods, several
studies have demonstrated that the concomitant use of HSM
aids in the proper identification of incompatibilities. Being a
visual thermal analysis technique, HSM allows efficient
monitoring of solid state interactions like possible dissolution
of one component into another that could be erroneously
interpreted as incompatibility by DSC. Secondly, the
degradation of one component is not masked by another
thermal event. Thus, the visual system enables possible
differentiation between solid state interactions and
incompatibilities. Requirement of very small quantity of
sample for visual observation is of great advantage when
performing compatibility studies.
4.2. Spectroscopic techniques [19, 20]
4.2.1. Vibrational spectroscopy
Fourier Transform Infrared, Raman and near Infrared
spectroscopy are sensitive to the structure and the environment
of organic compounds. These techniques are not only focused
on solid state behavior of APIs and their formulations, but are
also used as compatibility screening tool as the vibrational
changes serve as probe of potential intermolecular interactions
among the components. Thus, pharmaceutical interactions that
result in desalting, hydrate formation, dehydration,
polymorphic changes or transformation of crystalline to
amorphous forms and vice versa during processing can easily
be detected with the aid of these spectroscopic techniques.
However, the presence of overlapping peaks in the spectra
may hinder the analysis.
Thus, FT-IR helped in the choice of suitable excipients for a
stable formulation. DRIFT (diffuse reflectance infrared Fourier
transform infrared spectroscopy) is the most suitable technique
of the nondestructive spectroscopic methods and has attracted
interest, as the materials are not subjected to thermal or
mechanical energy during sample preparation, thereby
preventing solid state transformations.
4.2.2. Powder X-ray diffraction (PXRD) [21, 22]
It is a direct measure of the crystal form of a material with
atypical output being a plot of intensity vs the diffraction angle
(2θ). A crystalline material exhibits unique set of diffraction
peaks and the lack of crystalline API peaks when a dosage
 

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form is analyzed could indicate that the material is amorphous
or that the loading is too low to detect using the parameters
chosen. PXRD analysis is of immense help in case of
incompatibilities which occur during processes like
compression, wet granulation etc. and bring on change in
crystallinity/amorphicity and polymorphic forms of API in the
presence of excipients with/without adsorbed moisture.
4.2.3. Solid state nuclear magnetic resonance spectroscopy
(ssNMR) [23, 24]
Solid state NMR has shown immense potential in the
qualitative and quantitative analysis of pharmaceutical solids
(APIs and drug formulations) throws light on the chemical
bonding and composition of drug products, is highly selective
and offers limited interference from excipients as compared to
other traditional analytical techniques. It has a unique
advantage for detecting compatibility in crystalline as well as
amorphous components in a mixture. This technique probes
the existence of the drug–excipient interactions in the solid
state through variations in the chemical shift due to change in
the electron density at the interacting carbon atoms. Molecular
mobility of water in a drug–excipient system that influences
the chemical reactions can also be directly be measured by
nuclear magnetic resonance (NMR). Although, it possesses
numerous benefits over other spectroscopic techniques, the
data acquisition is lengthy and can be complicated in many
cases.
It is important to mention that weakly adsorbed water on the
excipients like starch, lactose, cellulose plays a significant role
in changing the molecular mobility within the system that
accelerates the chemical reactions. Nuclear magnetic
resonance (NMR) can directly measure the molecular mobility
of water and its correlation with the drug stability in a drug–
excipient mixture.
4.3. Microscopic technique
4.3.1. Scanning electron microscopy (SEM) [25]
This technique allows characterization of surface morphology
of materials and is useful especially when there are distinctive
differences in their crystal habits. It does not give any the
chemical structure/thermal behaviour of drug materials and
requires sample preparation along with stage condition setup.
However, the combination of SEM studies with other thermal
and spectroscopic techniques, such as DSC, HSM and FT-IR
offers some opportunities for the characterization of
incompatibilities of materials.
4.4. Chromatographic technique
4.1. High performance liquid chromatography [26, 27, 28]
This chromatographic technique is widely employed for
compatibility testing by quantitative estimation of drug
excipient samples that have been subjected to isothermal stress
testing (IST)]. IST involves the storage of drug alone and
drug–excipient blends with or without moisture at high
temperature for a specific period of time (about 3–4 weeks) to
accelerate any drug–excipient interaction. The chemical
incompatibility is then evaluated by determination of the drug
content in the stored samples. HPLC results that exhibit a
percentage loss similar to the drug considered individually
indicate no interaction between drug and the excipients and
vice versa. Sophisticated analytical techniques like liquid
chromatography mass spectrometry/mass spectrometry (LC–
MS/MS) have been used to further characterize the
incompatibility products. In spite of its optimal applicability,
~ 18 ~
HPLC technique is time consuming. Thus, preliminary search
of incompatibility using thermal techniques should be
corroborated with chromatography to finally establish the
chemical interactions of the API.
5. Predictive softwares (in-silico prediction) [31, 32]
5.1. CAMEO (Computer-Assisted Mechanistic Evaluation
of Organic reactions): Historical degradation predictions
involved the use of for modeling and predicting organic
chemical reactivity, software developed by William L.
Jorgensen. This software was discontinued, since predictions
often over looked secondary or ternary degradants, and its
major downfall was the inability to program the software with
new chemistry reactions.
5.2. DELPHI (Degradation Expert Leading to
Pharmaceutical Insight): It was another historical expert
system, capable of predicting reaction products under given
conditions. In contrast to CAMEO, DELPHI was specifically
designed to predict reactivity and degradation of molecules
and preceded beyond a primary reactive degradant to
subsequent degradants of degradants. Even though described
in the literature, DELPHI is a proprietary software system at
Pfizer that has been discontinued due to its inflexibility.
5.3. Zeneth: This in silico software released in 2010 is the
only commercially available program designed to predict
degradation pathways of pharmaceutical compounds. It was
developed by Lhasa Ltd. in consortium with a group of
pharmaceutical companies and based on the framework of
Meteor, a metabolite-prediction software program by Lhasa.
Zeneth contains a chemical engine allowing the description
and application of degradation transformations, a reasoning
engine allowing the description and application of degradant
transformation, a reasoning engine allowing assessment of
transformation likelihoods and graphical interface allowing
entry of query structures and display of prediction results.
Zeneth predicts degradation under the influence of reaction
conditions and optionally in the presence of other compounds
such as excipients.
Two of the main advantages of Zeneth are, total recall and the
absence of bias. A further major benefit is the steady
accumulation of knowledge about degradation chemistry in an
accessible form. Wet or bench chemistry is still needed and the
power of prediction can be harnessed to develop focused stress
testing protocols and to serve as a tool for the structure
elucidation scientist to match predicted degradant structures
with high performance LC-MS data.
6. Summary
Drug-excipient interactions/incompatibilities are major
concerns in formulation development. Selection of the proper
excipient during preformulation studies is of prime
importance. Many stability problems encountered during
development and post-commercialization can be ascribed to
inadequate matching of the ingredients in dosage forms, lack
of awareness of the complexities of chemical and physical
interactions, or the unheralded presence of a residue in one of
the excipients. Many such issues concern low levels of novel
entities formed by drug– excipient interactions that pose
questions concerning safety or tolerance.
Drug-excipient interactions may take a long time to be
manifested in conventional stability testing programmes, and
are not always predicted by stress and pre-formulation studies.
 

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They can complicate and compromise a development
programme or the viability of a commercial product. It is
possible to reduce the probability of such undesirable and
costly scenarios by allying knowledge of the propensity of a
drug to undergo degradation reactions with awareness of
excipient reactivity and of the residues that they may contain.
Thermo analytical and spectroscopic techniques have played a
pivotal role in characterization of solid state interactions and
early detection of drug–excipient compatibility. The in-depth
knowledge and appropriate use of these analytical techniques
have brought forth extraction of valuable information
concerning the drug–excipient interactions that aid in the
selection of appropriate excipients for stable and an efficacious
solid dosage form. In Non-thermal method of analysis HPLC
and FTIR gives reliable data for structural conformation. SEM
and Hot stage microscopy gives limited chemical information.
DSC and DTA results are not useful if thermal changes are
small, it should be confirmed using another non-thermal
method. In summary, knowledge of drug–excipient
interactions is a necessary prerequisite to the development of
dosage forms that are stable and of good quality.
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